In Vitro and In Vivo Pharmacodynamic Properties of Metoprolol in Fructose-fed Hypertensive Rats

Verniero, Carla Andrea Di; Silberman, Ezequiel A.; Mayer, Marc; Opezzo, Javier A.W.; Taira, Carlos A.; Höcht, Christián

doi:10.1097/fjc.0b013e3181730306

Cited by 16 publications

(9 citation statements)

References 39 publications

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“…However, it is noteworthy that both classes of drugs have been shown to be effective at reducing HR in vivo under conditions of increased HR. These include, for example, sympathetic stimulation and exercise as well as pathological conditions under which these drugs are normally prescribed in the clinic (1,14,19,24).With regard to the potential clinical relevance of this study, the lack of information in the literature about the impact of HRR per se on cardiac energy substrate metabolism created the impetus to characterize the acute effect of pure HRR by IVA in the isolated normoxic working healthy heart prior to its chronic effect being evaluated in a clinically relevant disease model for which potentially confounding factors such as cardiac gene remodeling will need to be considered (33,41). Despite the limitations of our study model, such as the basal conditions, absence of neuronal influence, and fixed compliance, we believe that this experimental model mimics to some extent the human transplanted heart, a condition for which IVA has been shown to be beneficial for the control of HR (16,27).…”

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confidence: 99%

Ivabradine reduces heart rate while preserving metabolic fluxes and energy status of healthy normoxic working hearts

Lauzier

Vaillant

Gélinas

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Heart rate reduction (HRR) is an important target in the management of patients with chronic stable angina. Most available drugs for HRR, such as β-blockers, have adverse effects, including on cardiac energy substrate metabolism, a well-recognized determinant of cardiac homeostasis. This study aimed at 1) testing whether HRR by ivabradine (IVA) alters substrate metabolism in the healthy normoxic working heart and 2) comparing the effect of IVA with that of the β-blocker metoprolol (METO). This was assessed using our well-established model of ex vivo mouse heart perfusion in the working mode, which enables concomitant evaluation of myocardial contractility and metabolic fluxes using 13 C-labeled substrates. Hearts were perfused in the absence (controls; n = 10) or presence of IVA (n = 10, 3 μM) with or without atrial pacing to abolish HRR in the IVA group. IVA significantly reduced HR (35 ± 5%) and increased stroke volume (39 ± 9%) while maintaining similar cardiac output, contractility, power, and efficiency. Effects of IVA on HR and stroke volume were reversed by atrial pacing. At the metabolic level, IVA did not impact on substrate selection to citrate formation, rates of glycolysis, or tissue levels of high-energy phosphates. In contrast, METO, at concentrations up to 40 μM, decreased markedly cardiac function (flow: 25 ± 6%; stroke volume: 30 ± 10%; contractility: 31 ± 9%) as well as glycolysis (2.9-fold) but marginally affected HR. Collectively, these results demonstrate that IVA selectively reduces HR while preserving energy substrate metabolism of normoxic healthy working mouse hearts perfused ex vivo, a model that mimics to some extent the denervated transplanted heart. Our results provide the impetus for testing selective HRR by IVA on cardiac substrate metabolism in pathological models.Address for reprint requests and other correspondence: C. Des Rosiers, Laboratory of Intermediary Metabolism, Montreal Heart Institute, Research Center, 5000 Bélanger St., Rm. 5350, Montreal, QC, Canada, H1T 1C8 (christine.des.rosiers@umontreal.ca CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptKeywords substrate metabolism; isolated working heart; ivabradine; β-blockers Heart rate reduction (HRR) is an important target in the management of patients with ischemic heart disease, a major cause of morbidity and mortality in developed countries (for reviews, see Refs. 6 and 45). Given their well-described beneficial effects on cardiovascular outcomes after myocardial infarction and in heart failure, β-blockers remain the first line treatment for many patients with ischemic heart disease (5, 12, 28). However, even new classes of β-blockers exhibit undesirable side effects on cardiac energy substrate metabolism (4, 28), which is now a well-recognized determinant of energy production, redox status, contractile function, ion fluxes, and oxygen consumption as well as hypertrophy development and progression to heart failure (33, 41).Specifically, acute administration of β-blockers to the isolated perfu...

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confidence: 99%

Ivabradine reduces heart rate while preserving metabolic fluxes and energy status of healthy normoxic working hearts

Lauzier

Vaillant

Gélinas

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…Further, increased reactive free radicals due to fructose feeding may also induce an increase in blood pressure [48, 49]. Studies in humans and animal models suggest a modest reduction in increased blood pressure with dietary antioxidants [48–50] with comparable responses to synthetic antihypertensive compounds such as captopril and metoprolol [51, 52]. …”

Section: Discussionmentioning

confidence: 99%

A Regenerative Antioxidant Protocol of Vitamin E and α‐Lipoic Acid Ameliorates Cardiovascular and Metabolic Changes in Fructose‐Fed Rats

Patel

Matnor

Iyer

et al. 2011

Evidence-Based Complementary and Alternative Medicine

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Type 2 diabetes is a major cause of cardiovascular disease. We have determined whether the metabolic and cardiovascular changes induced by a diet high in fructose in young adult male Wistar rats could be prevented or reversed by chronic intervention with natural antioxidants. We administered a regenerative antioxidant protocol using two natural compounds: α-lipoic acid together with vitamin E (α-tocopherol alone or a tocotrienol-rich fraction), given as either a prevention or reversal protocol in the food. These rats developed glucose intolerance, hypertension, and increased collagen deposition in the heart together with an increased ventricular stiffness. Treatment with a fixed combination of vitamin E (either α-tocopherol or tocotrienol-rich fraction, 0.84 g/kg food) and α-lipoic acid (1.6 g/kg food) normalized glucose tolerance, blood pressure, cardiac collagen deposition, and ventricular stiffness in both prevention and reversal protocols in these fructose-fed rats. These results suggest that adequate antioxidant therapy can both prevent and reverse the metabolic and cardiovascular damage in type 2 diabetes.

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“…Hypotensive effect Racemic metoprolol unbound plasma levels Effect-compartment model [54,83] Metoprolol Anesthetized dogs Chronotropic effect R-and S-metoprolol plasma levels Effect-compartment model [84] Metoprolol Hypertensive rats Chronotropic effect R-and S-metoprolol plasma levels Effect-compartment model [62] Metoprolol Rabbits with liver failure Chronotropic effect Racemic metoprolol plasma levels Effect-compartment model [73] Metoprolol Conscious normotensive rats…”

Section: Rs-carvedilol Plasma Levelsmentioning

confidence: 99%

“…Chronotropic effect Racemic metoprolol unbound plasma levels Effect-compartment model [54,83] Metoprolol Normotensive and hypertensive rats…”

Section: Rs-carvedilol Plasma Levelsmentioning

confidence: 99%

Models for evaluating the pharmacokinetics and pharmacodynamics for β-blockers

Höcht

Bertera

Mauro

et al. 2014

Expert Opinion on Drug Metabolism & Toxicology

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PK models and PK/PD modeling have clearly contributed to characterization of the PK and PD properties of β-blockers. Differences in cardiovascular actions between classical β-blockers and vasodilatory β-blockers need to be further studied in order to confirm the clinical benefits of the new-generation of β-blockers. PK/PD modeling may contribute to clarify the importance of heterogeneity of PK and PD properties of β-blockers potentially improving the selection of the adequate agent and dose regimen in the treatment of cardiovascular diseases.

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In Vitro and In Vivo Pharmacodynamic Properties of Metoprolol in Fructose-fed Hypertensive Rats

Abstract: Results demonstrate the beta1-adrenoceptors involvement in the fructose hypertension. A greater potency to metoprolol in vivo chronotropic effect was found in fructose-fed rats. This greater potency was not caused by alteration in the activity of beta1-adrenoceptors.

Cited by 16 publications

References 39 publications

Ivabradine reduces heart rate while preserving metabolic fluxes and energy status of healthy normoxic working hearts

Ivabradine reduces heart rate while preserving metabolic fluxes and energy status of healthy normoxic working hearts

A Regenerative Antioxidant Protocol of Vitamin E and α‐Lipoic Acid Ameliorates Cardiovascular and Metabolic Changes in Fructose‐Fed Rats

Models for evaluating the pharmacokinetics and pharmacodynamics for β-blockers

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